Mutations in WNT1 Cause Different Forms of Bone Fragility

2013 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​Mutations in WNT1 Cause Different Forms of Bone Fragility​
Keupp, K.; Beleggia, F.; Kayserili, H.; Barnes, A. M.; Steiner, M.; Semler, O. & Fischer, B. et al.​ (2013) 
American journal of human genetics92(4) pp. 565​-574​.​ DOI: https://doi.org/10.1016/j.ajhg.2013.02.010 

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Authors
Keupp, Katharina; Beleggia, Filippo; Kayserili, Hülya; Barnes, Aileen M.; Steiner, Magdalena; Semler, Oliver; Fischer, Björn; Yigit, Gökhan ; Janda, Claudia Y.; Becker, Jutta; Breer, Stefan; Altunoglu, Umut; Gruenhagen, Johannes; Krawitz, Peter; Hecht, Jochen; Schinke, Thorsten; Makareeva, Elena; Lausch, Ekkehart; Cankaya, Tufan; Caparros-Martin, Jose A.; Lapunzina, Pablo; Temtamy, Samia; Aglan, Mona; Zabel, Bernhard; Eysel, Peer; Koerber, Friederike; Leikin, Sergey; Garcia, K. Christopher; Netzer, Christian; Schoenau, Eckhard; Ruiz-Perez, Victor L.; Mundlos, Stefan; Amling, Michael; Kornak, Uwe ; Marini, Joan; Wollnik, Bernd 
Abstract
We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures. In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation. In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals. Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated beta-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Our finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis.
Issue Date
2013
Journal
American journal of human genetics 
ISSN
0002-9297

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